This invention relates to a process for preparing a compound of Formula I, 
wherein R1, R2, and Pt are as defined below, which can be used to prepare certain growth hormone secretagogues of Formula II below. This invention also relates to processes for preparing said growth hormone secretagogues.
The compounds of Formula II wherein R1 and R2 are as defined below are potent growth hormone secretagogues. These compounds and their preparation have been disclosed in International patent publication WO98/58947.
This invention is directed to a compound of Formula VII, 
wherein
Pt is an amine protecting group.
A preferred compound of Formula VII is the compound wherein Pt is Boc.
This invention is also directed to a process, designated Process A, for preparing a compound of Formula III, 
wherein
Pt is an amine protecting group;
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1 ;
A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N (X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94S(O)2N(X6)(X6), xe2x80x94N(X6)S(O)2-phenyl, xe2x80x94N(X6)S(O)2X6, xe2x80x94CONX11X12, xe2x80x94S(O)2NX11X12, xe2x80x94NX6S(O)2X12, xe2x80x94NX6CONX11X12, xe2x80x94NX6S(O)2NX11X12, xe2x80x94NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)r-L1-(CH2)rxe2x80x94;
L1 is C(X2)(X2), O, S(O)m or N(X2);
X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1 H-tetrazol-5-yl; or when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7 as a ring member;
r for each occurrence is independently 1, 2 or 3;
comprising reacting a compound of Formula IV, 
wherein R3 is (C1-C4)alkyl and Pt is as defined above,
with a preformed isocyanate or a carbonyl equivalent and R2NH2, wherein R2 is as defined hereinabove, in a reaction inert solvent for about one hour to about 72 hours at a temperature of about 0xc2x0 C. to about 80xc2x0 C.
A preferred process within Process A, designated Process B, comprises the process wherein R2 is hydrogen, (C1-C8)alkyl or xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with 1, 2 or 3 fluorine and wherein Pt is tert-butyloxycarbonyl.
A preferred process within Process B, designated Process C, comprises the process wherein said compound of Formula IV is reacted with a carbonyl equivalent selected from carbonyldiimidazole, phosgene, triphosgene and diphosgene.
A preferred process within Process C, designated Process D, comprises the process wherein said carbonyl equivalent is carbonyldiimidazole and said reaction inert solvent is methylene chloride.
A preferred process within Process D, designated Process E, comprises the process wherein R2 is methyl, ethyl or 2,2,2-trifluoroethyl.
An especially preferred process within Process E is the process wherein R2 is methyl.
Another especially preferred process within Process E is the process wherein R2 is ethyl.
Yet another especially preferred process within Process E is the process wherein R2 is 2,2,2-trifluoroethyl.
This invention is also directed to a process, designated Process F, for preparing a compound of Formula I, 
wherein
R1 is xe2x80x94(CH2)qN(X6)C(O)X6, xe2x80x94(CH2)qN(X6)C(O)(CH2)t-A1, xe2x80x94(CH2)qN (X6)S(O)2(CH2)t-A1, xe2x80x94(CH2)qN(X6)S(O)2X6, xe2x80x94(CH2)qN (X6)C(O)N(X6)(CH2)t-A1, xe2x80x94(CH2)qN (X6)C(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6 )(CH2)t-A1, xe2x80x94(CH2)qC(O)OX6, xe2x80x94(CH2)qC(O)O(CH2)t-A1, xe2x80x94(CH2)qOX6, xe2x80x94(CH2)qOC(O)X6, xe2x80x94(CH2)qOC(O)(CH2)t-A1, xe2x80x94(CH2)qOC(O)N (X6)(CH2)t-A1, xe2x80x94(CH2)qOC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)X6, xe2x80x94(CH2)qC(O)(CH2)t-A1, xe2x80x94(CH2)qN(X6)C(O)OX6, xe2x80x94(CH2)qN(X6)S(O)2N(X6)(X6), xe2x80x94(CH2)qS(O)mX6, xe2x80x94(CH2)qS(O)m(CH2)t-A1, xe2x80x94(C1-C10)alkyl, xe2x80x94(CH2)q-A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)q-Y1-(C1-C6)alkyl, xe2x80x94(CH2)q-Y1-(CH2)t-A1 or xe2x80x94(CH2)q-Y1-(CH2)txe2x80x94(C3-C7)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1 H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;
Y1 is O, S(O)m, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94N(X6)C(O)xe2x80x94, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)N(X6)xe2x80x94 or xe2x80x94OC(O)xe2x80x94;
q is 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
said (CH2)qgroup and (CH2)tgroup in the definition of R1 are optionally independently substituted with hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CON H2, xe2x80x94S(O)m(1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1 H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C1-C4)alkyl groups; and
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1;
where the alkyl groups and the cycloalkyl groups in the definition of R1 are optionally substituted with hydroxy, xe2x80x94C(O)OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94N (X6)(X6), xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)A1, xe2x80x94C(O)(X6), CF3, CN or 1, 2 or 3 independently selected halo groups;
A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94S(O)2N(X6)(X6), xe2x80x94N(X6)S(O)2-phenyl, xe2x80x94N(X6)S(O)2X6, xe2x80x94CONX11X12, xe2x80x94S(O)2NX11X12, xe2x80x94NX6S(O)2X12, xe2x80x94NX6CONX11X12NX6S(O)2NX11X12xe2x80x94NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)r-L1-(CH2)rxe2x80x94;
L1 is C(X2)(X2), O, S(O)m or N(X2);
X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1 H-tetrazol-5-yl; or
when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7 as a ring member;
r for each occurrence is independently 1, 2 or 3;
X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halo groups or 1-3 OX3 groups;
X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy;
m for each occurrence is independently 0, 1 or 2;
provided that X6 and X12 cannot be hydrogen when attached to C(O) or S(O)2 in the form C(O)X6, C(O)X12, S(O)2X6 or S(O)2X12; and
Pt is an amine protecting group;
comprising reacting a compound of Formula III, 
wherein Pt and R2 are as defined hereinabove, with an alkylating agent of formula R1-Z, wherein R1 is as defined hereinabove and Z is a leaving group, in the presence of a suitable base and a reaction inert solvent.
A preferred process within Process F, designated Process G, comprises the process wherein R1 is xe2x80x94(CH2)q-A1 or (C1-C7)alkyl; and R2 is hydrogen, (C1-C8)alkyl or xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with 1, 2 or 3 fluorine and wherein Pt is tert-butyloxycarbonyl.
A preferred process within Process G, designated Process H, comprises the process wherein Z in said alkylating agent is p-toluenesulfonyloxy, methanesulfonyloxy or halo; said base is alkaline metal bis(trimethylsilyl)amide or alkaline alkoxide; and said reaction inert solvent is N,N-dimethylformamide, tetrahydrofuran, toluene, isopropyl ether, MTBE or a mixture thereof.
A preferred process within Process H, designated Process I, comprises the process wherein R1 is xe2x80x94CH2-A1, Z is Cl, Br or 1, R2 is hydrogen or (C1-C3)alkyl optionally substituted with 1, 2 or 3 fluoro groups.
A preferred process within Process I, designated Process J, comprises the process wherein A1 is phenyl, pyridyl or thiazolyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH3, OCF2H, OCF3 and CF3; and R2 is methyl, ethyl or 2,2,2-trifluoroethyl.
An especially preferred process within Process J is the process wherein R1 is pyridin-2-ylmethyl or benzyl, where said benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl; and R2 is methyl.
Another especially preferred process within Process J is the process wherein R1 is pyridin-2-ylmethyl or benzyl, where said benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl; and R2 is ethyl.
Yet another especially preferred process within Process J is the process wherein R1 is pyridin-2-ylmethyl or benzyl, where said benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl; and R2 is 2,2,2-trifluoroethyl.
This invention is also directed to a process, designated Process K, for preparing a compound of Formula V, 
wherein
R1 is xe2x80x94(CH2)qN(X6)C(O)X6, xe2x80x94(CH2)qN(X6)C(O)(CH2)t-A1, xe2x80x94(CH2)qN(X6)S(O)2(CH2)t-A1, xe2x80x94(CH2)qN(X6)S(O)2X6, xe2x80x94(CH2)qN (X6)C(O)N(X6)(CH2)t-A1, xe2x80x94(CH2)qN(X6)C(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(CH2)t-A1, xe2x80x94(CH2)qC(O)OX6, xe2x80x94(CH2)qC(O)O(CH2)t-A1, xe2x80x94(CH2)qOX6, xe2x80x94(CH2)qOC(O)X6, xe2x80x94(CH2)qOC(O)(CH2)t-A1, xe2x80x94(CH2)qOC(O)N(X6)(CH2)t-A1, xe2x80x94(CH2)qOC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)X6, xe2x80x94(CH2)qC(O)(CH2)t-A1, xe2x80x94(CH2)qN(X6)C(O)OX6, xe2x80x94(CH2)qN(X6)S(O)2N(X6)(X6), xe2x80x94(CH2)qS(O)mX6, xe2x80x94(CH2)qS(O)m(CH2)t-A1, xe2x80x94(C1-C10)alkyl, xe2x80x94(CH2)q-A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)q-Y1-(C1-C6)alkyl, xe2x80x94(CH2)q-Y1-(CH2)t-A1 or xe2x80x94(CH2)q-Y1-(CH2)t-(C3-C7)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1 H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;
Y1 is O, S(O)m, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94N(X6)C(O)xe2x80x94, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)N(X6)xe2x80x94 or xe2x80x94OC(O)xe2x80x94;
q is 1, 2, 3 or 4;
tis 0, 1, 2or 3;
said (CH2)q group and (CH2)t group in the definition of R1 are optionally independently substituted with hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C1-C4)alkyl groups; and
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1;
where the alkyl groups and the cycloalkyl groups in the definition of R1 are optionally substituted with hydroxy, xe2x80x94C(O)OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94N(X6)(X6), xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)A1, xe2x80x94C(O)(X6), CF3, CN or 1, 2 or 3 independently selected halo groups;
A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94S(O)2N(X6)(X6), xe2x80x94N(X6)S(O)2-phenyl, xe2x80x94N(X6)S(O)2X6, xe2x80x94CONX11X12, xe2x80x94S(O)2NX11, X12, xe2x80x94NX6S(O)2X12, xe2x80x94NX6CONX11, X12, xe2x80x94NX6S(O)2NX11X12, xe2x80x94NX6C(O)X12 imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)r-L1-(CH2)rxe2x80x94;
L1 is C(X2)(X2), O, S(O)m or N(X2);
X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1H-tetrazol-5-yl; or
when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7 as a ring member;
r for each occurrence is independently 1, 2 or 3;
X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halo groups or 1-3 OX3 groups;
X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy;
m for each occurrence is independently 0, 1 or 2; provided that X6 and X12 cannot be hydrogen when attached to C(O) or S(O)2 in the form C(O)X6, C(O)X12, S(O)2X6 or S(O)2X12;
comprising reacting a compound of Formula I, 
wherein
Pt is an amine protecting group and R1 and R2 are as defined hereinabove;
with an acid in the presence of a reaction inert solvent.
A preferred process within Process K, designated Process L, comprises the process wherein R1 is xe2x80x94(CH2)q-A1 or (C1-C7)alkyl; and R2 is hydrogen, (C1-C8)alkyl or xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with 1, 2 or 3 fluorine and wherein Pt is t-butyloxycarbonyl.
A preferred process within Process L, designated Process M, comprises the process wherein said acid is methanesulfonic acid, and said reaction inert solvent is methylene chloride.
A preferred process within Process M, designated Process N, comprises the process wherein is R1 is xe2x80x94CH2-A1; and R2 is hydrogen or (C1-C3)alkyl optionally substituted with 1, 2 or 3 fluoro groups.
A preferred process within Process N, designated Process O, comprises the process wherein R1 is xe2x80x94CH2-A1 where A1 is phenyl, pyridyl or thiazolyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH3, OCF2H, OCF3 and CF3; and R2 is methyl, ethyl or 2,2,2-trifluoroethyl.
An especially preferred process within Process O comprises the process wherein R1 is pyridin-2-ylmethyl or benzyl, where said benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl and particularly where said benzyl is substituted with up to two fluoro; and R2 is methyl. Still more especially preferred within this process is the process wherein R1 is benzyl and R2 is methyl or where R1 is pyridin-2-ylmethyl and R2 is methyl.
Another especially preferred process within Process O comprises the process wherein R1 is pyridin-2-ylmethyl or benzyl, where said benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl; and R2 is ethyl. Still more especially preferred within this process is the process wherein R1 is benzyl and R2 is ethyl or where R1 is pyridin-2-ylmethyl and R2 is ethyl.
Yet another especially preferred process within Process O comprises the process wherein R1 is pyridin-2-ylmethyl or benzyl, where said benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl; and R2 is 2,2,2-trifluoroethyl. Still more especially preferred within this process is the process wherein R1 is benzyl and R2 is trifluoroethyl or where R1 is pyridin-2-ylmethyl and R2 is trifluoroethyl.
This invention is also directed to a process, designated Process P, for preparing a compound of Formula XIII, 
comprising:
(a) reacting piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-(C1-C4)alkyl ester with a carbonyl equivalent and 2,2,2-trifluoroethylamine in the presence of a reaction inert solvent to form the compound of Formula XIV, 
(b) reacting said compound of Formula XIV with 2-picolyl-Z1, wherein Z1 is halo, methanesulfonyloxy or p-toluenesulfonyloxy, in the presence of a base and a reaction inert solvent to form the compound of Formula XV, 
(c) reacting said compound of Formula XV with an acid in the presence a reaction inert solvent.
A preferred process within Process P, designated Process Q, comprises the process wherein in step (a), said carbonyl equivalent is N,Nxe2x80x2-carbonyldiimidazole, phosgene, diphosgene or triphosgene and said reaction inert solvent is methylene chloride; in step (b), said alkylating agent is 2-picolyl chloride, said base is potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium amide, potassium amide, sodium (C1-C4)alkoxide or potassium (C1-C4)alkoxide and said reaction inert solvent is a mixture of tetrahydrofuran and N,N-dimethylformamide; and in step (c), said acid is methanesulfonic acid and said reaction inert solvent is methylene chloride.
A preferred process within Process Q is the process wherein in step (a), said carbonyl equivalent is N,Nxe2x80x2-carbonyldiimidazole; and in step (b), said base is potassium bis(trimethylsilyl)amide.
This invention is also directed to a process, designated Process R, for preparing a compound of Formula VI, 
comprising
(a) reacting a compound of Formula IV, 
wherein Pt is an amine protecting group and R3 is (C1-C4)alkyl, with a carbonyl equivalent and CF3CH2NH2 in a reaction inert solvent to form a compound of Formula VII, 
wherein Pt is as defined hereinabove;
(b) reacting said compound of Formula VII with 2-picolyl-Z1, wherein Z1 is halo, methanesulfonyloxy or p-toluenesulfonyloxy, in the presence of a base and a reaction inert solvent at a temperature from about xe2x88x9278xc2x0 C. to about 25xc2x0 C. for from about one hour to about 24 hours to form a compound of Formula VIII, 
wherein Pt is as defined above;
(c) reacting said compound of Formula VIII with a suitable acid in a reaction inert solvent at a temperature from about xe2x88x9230xc2x0 C. to about 25xc2x0 C. for from about one hour to about 10 hours to form a compound of Formula IX, 
(d) resolving said compound of Formula IX with D-tartaric acid in a reaction inert solvent to form the D-tartrate salt of a compound of Formula X, 
(e) reacting said D-tartrate salt of a compound of Formula X with a compound of Formula XI, 
wherein Boc is tert-butyloxycarbonyl, a peptide coupling reagent and a base in a reaction inert solvent to form a compound of Formula XII, 
(f) reacting said compound of Formula XII under standard t-butyloxycarbonyl group removing conditions to form a compound of Formula VI, 
A preferred process within Process R, designated Process S, is the process wherein:
in step (a), said carbonyl equivalent is N,Nxe2x80x2-carbonyldiimidazole, phosgene, diphosgene or triphosgene;
in step (b), said base is potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium amide, potassium amide, sodium (C1-C4)alkoxide or potassium (C1-C4)alkoxide and
in step (e), said peptide coupling reagent is EEDQ, EDC, DCC or 1-propanephosphonic acid cyclic anhydride;
A preferred process within Process S, designated Process T, is the process wherein:
in step (a), said carbonyl equivalent is N,Nxe2x80x2-carbonyldiimidazole and said reaction inert solvent is methylene chloride;
in step (b), said base is potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and said reaction inert solvent is N,N-dimethylformamide, toluene, tetrahydrofuran or a mixture thereof;
in step (c), said acid is methanesulfonic acid and said reaction inert solvent is methylene chloride;
in step (d), said reaction inert solvent is a mixture of acetone and water;
in step (e), said peptide coupling reagent is 1-propanephosphonic acid cyclic anhydride, said base is triethylamine and said reaction inert solvent is ethyl acetate; and
in step (f), said standard t-butyloxycarbonyl group removing conditions comprise using hydrochloric acid in methanol.
This invention is particularly directed to a process of Process T wherein 2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide is prepared.
The preparation of the intermediates of Formula I of this invention can be readily carried out as set forth below. The processes of this invention, e.g., to prepare the compounds of Formulas I, II and VI are also set forth in detail below.
In the structural formulas disclosed throughout the instant specification and claims, the following terms have the indicated meanings unless expressly stated otherwise:
The alkyl groups are intended to include those alkyl groups of the designated length in either a straight or branched configuration which may optionally contain one or more double or triple bonds. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, ethynyl, propenyl, butadienyl, hexenyl and the like.
When the definition C0-alkyl occurs in the definition, it means a single covalent bond.
The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration which may optionally contain one or more double or triple bonds. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, 2-propynyloxy, isobutenyloxy, hexenyloxy and the like.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d is intended to include the halogen atoms fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
The term xe2x80x9chalogenated alkylxe2x80x9d is intended to include an alkyl group as defined above substituted by one or more halogen atoms as defined above.
The term xe2x80x9chalogenated cycloalkylxe2x80x9d is intended to include a cycloalkyl group substituted by one or more halogen atoms as defined above.
The term xe2x80x9carylxe2x80x9d is intended to include phenyl, naphthyl, aromatic 5-membered rings with one to four heteroatoms, aromatic 6-membered rings with one to four heteroatoms and fused 5- and/or 6-membered bicyclic rings with one to four heteroatoms of nitrogen, sulfur or oxygen. Examples of such heterocyclic aromatic rings are pyridine, thiophene, furan, benzothiophene, tetrazole, indole, N-methylindole, dihydroindole, indazole, N-formylindole, benzimidazole, thiazole, pyrimidine, and thiadiazole.
The term xe2x80x9ccarbonyl equivalentxe2x80x9d means a compound containing two leaving groups attached directly to a carbonyl moiety. When a carbonyl equivalent is reacted with two nucleophiles, said nucleophiles displace both leaving groups resulting in the insertion of a carbonyl group between the two nucleophiles. Preferred carbonyl equivalents include carbonyldiimidazole, phosgene, diphosgene and triphosgene. A particularly preferred carbonyl equivalent is carbonyldiimidazole.
The term xe2x80x9cpreformed isocyanatexe2x80x9d means an isocyanate which is used as a reagent as opposed to an isocyanate which is formed in situ. An example of a preformed isocyanate is methyl isocyanate.
In this specification the following abbreviations are used with the following meanings:
Certain of the above defined terms may occur more than once in the various structural formulas set forth herein. Upon each occurrence such terms shall be defined independently of any others.
The process of the instant invention is readily carried out as described below. 
According to Scheme 1, the compounds of Formula III wherein Pt is an amine protecting group and R2 is as defined above may be prepared from piperazine-2-carboxylate esters of formula 1xe2x80x941 wherein R3 is (C1-C4)alkyl. For example, ethyl piperazine-2-carboxylate is protected under standard conditions well known to those skilled in the art with a suitable amine protecting group to afford the compound of Formula IV wherein R3 is ethyl, which is reacted with a preformed isocyanate or an amine of formula R2-NH2 and a carbonyl equivalent such as carbonyldiimidazole, phosgene, diphosgene or triphosgene to afford the compound of Formula III.
Any amine protecting group known to those skilled in the art of peptide chemistry can be utilized according to Scheme 1 to protect the 4-position of the piperazine ring. Among the protecting groups, Boc is preferably used for its stability to subsequent reaction conditions. For example, protection of the 4-amino group of ethyl piperazine-2-carboxylate with Boc can be carried out according to procedures well known to those skilled in the art. For example, ethyl piperazine-2-carboxylate is reacted with di-tert-butyl dicarbonate in the presence of a base such as triethylamine, 4-dimethylaminopyridine, diisopropylethylamine, potassium hydroxide or sodium hydroxide. This reaction can be carried out at a temperature from about 0xc2x0 C. to about 80xc2x0 C. for from about one hour to about 24 hours. Preferably protection of the amine is carried out at 0xc2x0 C. in methylene chloride.
The compound of Formula IV is reacted with an amine of formula R2xe2x80x94NH2 and a carbonyl equivalent in the presence of a suitable tertiary amine in a reaction inert solvent at a temperature from about 0xc2x0 C. to about 80xc2x0 C. for from about one hour to about 72 hours. A suitable reaction inert solvent is methylene chloride. Suitable carbonyl equivalents include carbonyldiimidazole, phosgene, diphosgene and triphosgene. Carbonyl diimidazole is particularly preferred. Suitable tertiary amines include triethylamine and diisopropylethylamine. Triethylamine is particularly preferred. The compound of Formula IV may also be reacted with an isocyanate, such as methyl isocyanate in a reaction inert solvent at from about room temperature to about 60xc2x0 C. A suitable solvent is refluxing acetone. 
According to Scheme 2, the intermediate compounds of Formula I are prepared from compounds of Formula III. For example, a compound of Formula III is reacted with an alkylating agent of the formula R1xe2x80x94Z wherein R1 is as defined above and Z is a suitable leaving group in the presence of a suitable base to give the compound of Formula I. Suitable leaving groups include methanesulfonyloxy, p-toluenesulfonyloxy and halo. In a particularly preferred pathway, R1xe2x80x94Z is 2-picolyl chloride. Suitable bases include alkaline amides and alkaline (C1-C4)alkoxides such as sodium ethoxide, sodium methoxide, potassium t-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide. The alkylation reaction is carried out in a reaction inert solvent such as N,N-dimethylformamide, tetrahydrofuran, diethyl ether, toluene and the like. The reaction is carried out at about xe2x88x9278xc2x0 C. to about 25xc2x0 for about one hour to about 24 hours. When the alkylating agent contains a ring nitrogen atom, such as 2-picolyl chloride, it is preferred to use the free base form of the alkylating agent.
After alkylation is complete, the amine protecting group (Pt) of the compound of Formula I is removed by performing deprotection procedures well known to those skilled in the art. When Pt is CBZ, for example, the CBZ group is removed by hydrogenation over a catalyst. An acid such as hydrochloric acid or trifluoroacetic acid may be added to the hydrogenation mixture to ensure complete reaction. It is preferred that a palladium catalyst is used in the removal of CBZ groups.
Alternatively, when Pt is Boc, which is the preferred protecting group, the skilled person may treat the compound of Formula I with an acid to effect deprotection. Preferred acids for such deprotections include trifluoroacetic acid, methanesulfonic acid and dilute hydrochloric acid. It is particularly preferred to deprotect the instant Boc-protected amine by treating the compound of Formula III with methanesulfonic acid in a polar solvent such as methanol, ethanol and dichloromethane at a temperature from about xe2x88x9230xc2x0 C. to about 25xc2x0 C. for about one hour to about 24 hours.
The compounds of Formula V thus prepared are obtained in racemic form. Optical resolution of the compounds of Formula V can be carried out to afford compounds of Formula X according to the procedures set forth in Scheme 3.
According to Scheme 3, a compound of Formula V is resolved into its separate optically active enantiomer of Formula X by treating a compound of Formula V with D-tartaric acid in a suitable mixed solvent system comprising a polar organic solvent and water (e.g., ketone/water such as acetone/water or alcohol/water such as methanol/water). The resulting diastereomers are separated by methods well known to those skilled in the art. 
According to Scheme 4, a compound of Formula X is condensed with a compound of Formula XIV to yield a compound of Formula XV. This condensation is performed in the presence of a suitable peptide coupling reagent such as EEDQ, EDC, DCC or PPAA and a base such as triethylamine or diisopropylethylamine in a reaction inert solvent at a temperature of about xe2x88x9255xc2x0 C. to about 0xc2x0 C. for about one half hour to about eight hours. Preferred reaction inert solvents include ethyl acetate, tetrahydrofuran and methylene chloride. Ethyl acetate is particularly preferred. PPAA is a particularly preferred peptide coupling reagent. A particularly preferred base is triethylamine. Typically, the protecting group (P) on the compound of Formula XIV is Boc, which is removed as set forth above or according to other procedures well known to those skilled in the art such as those procedures set forth in Protecting Groups in Organic Synthesis, Greene and Wuts, Eds., (John Wiley and Sons, New York, 1991).
The compound of Formula X can be used in its free-base in this condensation. The free-base form of the compound of Formula X can be formed by treating a compound of Formula X with ammonium hydroxide or aqueous sodium bicarbonate. 
As illustrated in Scheme 5, an intermediate ether of formula 5-2 can be prepared by treating an amino acid of formula 5-1, where Pt is a suitable protecting group, with a base such as potassium carbonate or sodium hydride followed by benzyl mesylate, benzyl tosylate or a benzyl halide, such as benzylbromide, in a suitable solvent such as DMF or THF. Deprotection of the amine transforms 5-2 into 5-3.
As illustrated in Scheme 6, intermediates of formula 6-2 can be prepared by treating an acid of formula 6-1 with hydroxysuccinimide in the presence of a coupling agent such as EDC in an inert solvent such as methylene chloride. Treating 6-2 with an amino acid of formula 5-3 at about room temperature in a solvent such as DMF in the presence of a base such as diisopropylethylamine or triethylamine produces compounds of formula XI.
(C1-C4)Alkyl piperazine-2-carboxylates can be synthesized according to procedures well known to those skilled in the art such as the procedure set forth in Synthesis, 1992, 1065-1066. For example, ethyl piperazine-2-carboxylate can be prepared by coupling ethyl 2,3-dibromopropionate and N,Nxe2x80x2-dibenzylethylene diamine according to known alkylation methods. This reaction is typically performed in the presence of a base such as triethylamine in a reaction inert solvent at a temperature from about 25xc2x0 C. to about 100xc2x0 C. for about one hour to about 24 hours, preferably under nitrogen. A particularly preferred solvent for this reaction is toluene. The N-benzyl groups can be removed by hydrogenation to afford alkyl piperazine-2-carboxylates.
Alternatively, (C1-C4)alkyl piperazine-2-carboxylates can be prepared by esterification of piperazine-2-carboxylic acid with ethanol in the presence of a suitable acid catalyst such as sulfuric acid, hydrogen chloride or p-toluenesulfonic acid results in the formation of ethyl piperazine-2-carboxylate (e.g., M. D. Armstrong et al., J. Am. Chem. Soc., 77:6049-6051; (1955)).
The compounds of Formula II prepared by the processes of the instant invention all have at least two asymmetric centers as noted by the wedge-shaped bonds in the structural formula. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure of partially purified optical isomers, racemic mixtures or diastereomeric mixtures thereof, be included in the compounds represented by Formula II.
The compounds of Formula II and VI prepared by the processes of this invention are generally isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, D-tartaric, L-tartaric, malonic, methane sulfonic and the like. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter-ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
The pharmaceutically acceptable salts are formed by taking about 1 equivalent of a compound of Formula II and contacting it with about 1 equivalent of the appropriate corresponding acid of the salt which is desired. Work-up and isolation of the resulting salt is well-known to those of ordinary skill in the art.
As disclosed in commonly assigned International Application Number PCT/IB98/00873, the growth hormone secretagogues of Formula II prepared by the processes of this invention are useful in vitro as unique tools for understanding how growth hormone secretion is regulated at the pituitary level. As such the compounds of Formula II are useful for all of the utilities set forth therein and may be administered as set forth therein. Further, dosages of the compounds of Formula II may be determined as set forth therein.
Many protected amino acid derivatives are commercially available, where the amine protecting groups are, for example, Boc, CBZ, FMOC, benzyl or ethoxycarbonyl groups. Other protected amino acid derivatives can be prepared by literature methods well-known to one skilled in the art. Some substituted piperazines and piperidines are commercially available, and many other piperazines and 4-substituted piperidines are known in the literature. Various heterocyclic substituted piperidines and piperazines can be prepared following literature methods using derivatized heterocyclic intermediates. Alternatively, the heterocyclic rings of such compounds can be derivatized by standard means, such as coupling with CDI, hydrogenation of aromatic heterocycles, etc. as is well-known to those skilled in the art.
Many of the reactions of this invention concern compounds which contain amine protecting groups (Pt), which can be any suitable protecting group known to those skilled in the art. Benzyloxycarbonyl groups can be removed by a number of methods including, catalytic hydrogenation with hydrogen in the presence of a palladium or platinum catalyst in a protic solvent such as methanol. Preferred catalysts are palladium hydroxide on carbon or palladium on carbon. Hydrogen pressures from 1-1000 psi can be employed; pressures from 10 to 70 psi are preferred. Alternatively, the benzyloxycarbonyl group can be removed by transfer hydrogenation.
Removal of Boc protecting groups can be carried out using a strong acid such as trifluoroacetic acid, methanesulfonic acid or hydrochloric acid with or without the presence of a cosolvent such as dichloromethane or methanol at a temperature of about xe2x88x9230xc2x0 C. to about 70xc2x0 C., preferably about xe2x88x925xc2x0 C. to about 35xc2x0 C.
Benzyl groups on amines can be removed by a number of methods including catalytic hydrogenation with hydrogen in the presence of a palladium catalyst in a protic solvent such as methanol. Hydrogen pressures from 1-1000 psi can be employed; pressures from 10 to 70 psi are preferred. The addition and removal of these and other protecting groups are discussed in detail by T. Greene in Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981.
General Procedure A: (Cleavage of a Boc-protecting group from a Boc-protected amine using concentrated HCl): The Boc-protected amine is dissolved in a minimum volume of ethanol and the resulting solution is cooled to about 0xc2x0 C. and concentrated HCl (typically about 1 to 4 mL per mmol of Boc-procted amine) is added and the reaction mixture is warmed to room temperature and stirred for about one hour to about 2.5 hours (or the time required for complete disappearance of the starting material to a more polar product as judged by thin layer chromatography). The resulting solution or suspension is concentrated and the residue is coevaporated several times with added ethanol to afford the amine hydrochloride which is used without further purification or purified as specified.